Project Summary/Abstract My major research interest is to understand molecular mechanisms of gene regulation and function in the pathogenesis of cancer and cardiovascular disease, two major health burdens for our Veterans. We seek to determine the fundamental molecular signals that regulate cellular function, and translate the findings in the pathogenesis of disease using animal models, so as to identify novel molecular targets and strategies for prevention and intervention of disease. Translational research on cancer pathogenesis and resistance to therapy. We have been focused on the death receptor signaling pathways in regulating apoptosis of cancer cells and their roles in cancer tumorigenesis and resistance to therapy. Our studies have demonstrated that modulating the Death- Inducing Signaling Complex (DISC) determines the downstream survival and apoptosis signals. Recently, we discovered a novel regulator, poly(ADP-ribose) polymerase 1 (PARP1), in the death receptor-5 DISC that contribute to the resistance of pancreatic cancer to therapy, a critical hurdle for effective cancer treatment. Based on this novel finding, our current VA merit review award (2014-2018) is to delineate the mechanisms underlying DISC-associated PARP1 in regulating pancreatic cancer resistance to antibody immunotherapy with a humanized anti-death receptor 5 antibody (TRA-8/CS1008). I will continue my long-term collaboration with VA physician scientist, Jay M McDonald, MD (Pathology, Birmingham VA) and the inventor of TRA-8/CS1008, Tong Zhou, MD (Medicine, UAB). As CS1008 therapy has been effective in clinical trials for some cancer but resistant in others including pancreatic tumors, the overarching goal for our investigations is to elucidate the molecular mechanisms and identify new compounds that sensitize pancreatic cancer to TRA-8-induced apoptosis, thus overriding drug resistance and leading to successful therapies. Differentiation and reprogramming of vascular smooth muscle cells in vascular disease. Phenotypic plasticity of vascular smooth muscle cells (VSMC) provides an excellent model to study the function of cell differentiation in health and disease. We are particularly interested in studying how VSMC become bone-like cells (vascular calcification). Using tissue-specific gene knockout mouse models, we have demonstrated an essential role of the osteogenic transcription factor Runx2 in regulating vascular calcification, a feature of atherosclerosis, diabetes and end stage renal disease. We have uncovered novel mechanisms underlying Runx2 upregulation in the vasculature by increased oxidative stress and hyperglycemia. We have also discovered a novel crosstalk between VSMC, macrophages and vascular stem cells in the development of atherosclerotic calcification. We have published a body of work demonstrating a critical integrative role of Runx2 upregulation in VSMC in promoting vascular pathology, which has been highly recognized and cited. Our overarching goals are to identify novel mechanisms that regulate pathogenesis of vascular calcification and identify therapeutic targets. We have brought together several physician scientists at the Birmingham VA including Drs. Paul Sanders and Anupam Agarwal (Nephrology) as well as Dr. Louis Dell'Italia (Cardiology and Associate Chief of Staff). Our collaborative studies have led to the development of a Program Project to investigate ?Novel Regulators for Vascular Disease?, which have been supported by the VA (2012-2016). These investigations will not only elucidate the fundamental molecular mechanisms underlying the regulation of cancer drug resistance and pathogenesis of vascular disease, but also provide novel molecular insights facilitating further studies to translate these findings into therapeutic strategies for patient care, so as to improve the Veterans' health, life span and quality of life.